We propose to work in four areas to characterize the effect of epidermal growth factor (EGF) on the control of cell multiplication in culture: the physical properties of growth factor-cell interaction, the biological response of cells, the specific changes occurring in neoplasia and aging, and the genetic control of growth factor cell receptors. Availability of purified EGF presents the first real opportunity to study the specific binding of a general growth stimulating factor to cells in culture and to define the biological parameters of growth, i.e., DNA, RNA, protein synthesis and mitosis, in relation to binding efficiency. Our basic hypothesis is that the stoichiometric serum requirements of cells in culture may be explained by their relative ability to bind growth factors. Our studies will examine EGF affinity for virus transformed cells as a means to explain their strikingly decreased serum requirement and to understand the role of growth factors in neoplastic growth. Evaluation of EGF binding to normal aging human fibroblasts as well as cells from patients suffering from conditions causing premature senescence may offer functional parameters for assessing cell aging in culture and allow us to evaluate clinical senescence in man. These data are likely to provide information about the genetic control of the aging process and suggest means to rejuvenate (rescue) senescent cells. Selected use of inhibitors of nucleic acid and protein metabolism in synchronized cultures will increase our knowledge of the genetic modulation of the membrane receptors for EGF in normal, neoplastic and aging cell systems. Hybridization of cells with markedly disparate EGF affinities should permit further clarification of the genetic control of cellular receptors for growth factors; mouse x human hybrids preferentially lose human chromosomes and thus, with appropriate clonal selection and karyotype analyses, autosomal genes regulating EGF receptor proteins may be localized to specific human chromosomes. Increasing our knowledge about how cell growth, and ultimately the organism, is controlled brings us closer to an appreciation of those factors limiting man's life-span and may provide clues to the control and prevention of neoplasia.